CN115298172B - Salt form and crystal form of SMO inhibitor compound and preparation method thereof - Google Patents

Salt form and crystal form of SMO inhibitor compound and preparation method thereof Download PDF

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CN115298172B
CN115298172B CN202180022477.8A CN202180022477A CN115298172B CN 115298172 B CN115298172 B CN 115298172B CN 202180022477 A CN202180022477 A CN 202180022477A CN 115298172 B CN115298172 B CN 115298172B
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xrpd pattern
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CN115298172A (en
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陈小新
谭珍友
张振锋
刘呈武
张兰
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Guangdong Xianqiang Pharmaceutical Co ltd
Guangdong Zhongsheng Pharmaceutical Co Ltd
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Guangdong Zhongsheng Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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Abstract

A salt form and a crystal form of an SMO inhibitor compound are specifically disclosed, wherein the crystal form I of the compound 1 has an XRPD pattern with diffraction peaks at 3.7,7.4,10.2,12.0,13.3,14.1,14.6,14.9,15.5,16.2,18.4,18.8,19.5,20.5,21.0,22.5,23.7,24.1,25.3,26.7,28.2 +/-0.2 DEG of 2 theta, and a plurality of crystal forms of the compound 2 are disclosed, and the compound 2 is a salt obtained after the compound 1 is combined with sulfuric acid. The crystal forms of the compound 1 and the compound 2 disclosed by the invention have the characteristic of high stability, and have a considerable patent medicine prospect; is favorable for preparing anticancer drugs. The structural formula of compound 1 is shown below:

Description

Salt form and crystal form of SMO inhibitor compound and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and in particular relates to a salt form and a crystal form of an SMO inhibitor compound, a preparation method thereof, and a bulk drug and a pharmaceutical composition containing the crystal form and the salt form.
Background
The Hedgehog (Hh) signaling pathway regulates processes such as proliferation, differentiation, and tissue formation of cells, and plays a critical role in embryonic development. In adult tissues, the activation of the Hh signal channel has important functions in stem cell regulation, tissue injury repair, tumor generation and the like. GLI1 acts as a transcription factor for Hh signaling pathway and as a target gene, and its abnormal activation leads to the development of many common tumors, such as basal cell carcinoma and medulloblastoma. Therefore, finding the key protein for regulating GLI1 and even the whole signal path has very important theoretical guiding significance for clinical treatment of related tumors.
SMO receptors are key signal transducers in Hh signaling pathways, belonging to the class F G protein-coupled receptors. SMO receptors are responsible for maintaining normal development of embryos, an abnormality of this protein associated with cancer. The Hh ligand (SonVc, vndVan or Desert) binds to transmembrane receptor fragment protein-1 (PTCH-1), releasing SMO inhibition, activating the downstream GLI zinc finger transcription factor (GLI 1, 2 or 3). In embryonic development, the Hh pathway is essential for regulating cell proliferation and differentiation, but is silenced in most adult tissues. SMO-associated signaling pathways are GPCR signaling and cancer signaling pathways. It was found in solid tumors that mutations such as SMO genomic variation, PTCH1 gene silencing variation, hh ligand overexpression, and SMO gene activation mutations all lead to aberrant activation of SMO and Hh signaling pathways, exerting a tumorigenic effect by improving tumor microenvironment, promoting angiogenesis and tumor migration. The Hh signaling pathway enhancement by SMO activating mutations is associated with basal cell carcinoma and medulloblastoma. SMO gene amplification occurs in a variety of tumors such as ovarian cancer, melanoma, glioma, and the like. Vismodigib (GDC-0449) is a novel oral drug with selective Hedgehog signaling pathway. Manufactured by Genentech, roche, gene technology company (Genentech), has been approved by the FDA for the treatment of basal cell carcinoma, which was the first drug approved for the treatment of basal cell carcinoma since the history. Biochemical research shows that the inhibition point of the Vismodygib is on SMO, and the activity of the SMO is inhibited, so that the activity of the whole Hh channel is inhibited, and the purpose of resisting cancer is achieved. In addition to basal cell carcinoma, many other cancers are associated with the ultra-high viability of the Hh signaling pathway, including medulloblast, pancreatic, intestinal, rectal, ovarian, and prostate cancers, as well as partial blood cancers, and the like (De Smallee E.et al Curr OpVn VnvesVg drugs.2010;11 (6): 707-18). Therefore, the prospect of developing Hh inhibitors as novel anticancer drugs is very wide.
Although some SMO inhibitors already exist in the prior art, they are subject to improvement in terms of activity, solubility, pharmacokinetics, drug formation, etc.
Patent WO2015144001 discloses a series of quinoline derivatives. In vitro activity data indicated that some compounds were significantly effective in inhibiting Hh pathway, including compound WX298 (compound 1). Patent WO2017050224 discloses a crystal form compound of free base of quinoline derivative WX298 and its dihydrate disulfate, wherein, the dihydrate disulfate crystal form C is placed for 10 days at a temperature of 40 ℃/75% rh, the crystal form is still unchanged, and is placed for 10 days at a high temperature and a high humidity, the impurity content is not obviously increased, and the impurity content is obviously increased, and the appearance shape is also changed along with the placement under strong light, so that a salt form and a crystal form with better stability are searched, and more easy preparation, more stable intermediate products and/or bulk drugs are provided for subsequent drug development, and the method has great significance for drug development.
Disclosure of Invention
The novel crystal forms of the SMO inhibitor compound (compound 1 and compound 2) provided by the invention are good in drug property (such as stability, fluidity, compressibility and the like), and provide various raw material drug selections for subsequent drug development.
The present invention relates to a range of crystalline forms of SMO inhibitor compounds including, but not limited to, non-solvates and solvates of SMO inhibitor compounds, the "solvents" in the "non-solvates and solvates" including water and organic solvents including, but not limited to, methanol, ethanol, propanol, isopropanol, acetone, butanone, acetonitrile, dichloromethane, chloroform, ethyl acetate, and the like, as is common in the art.
For characterization of the crystal form of SMO inhibitor compounds, those skilled in the art will appreciate that for a particular crystal form of a particular compound, the 2 theta angle of each diffraction peak in its X-ray powder diffraction pattern (XRPD) will have a range of fluctuation in repeated experiments, typically within ±0.2°, due to the influence of instrumentation, methods of operation, sample purity, artifacts, etc. during the characterization process; in addition, as can be understood by those skilled in the art, the stability and repeatability of the diffraction peaks can be affected by the factors such as the 2 theta angle and the absorption intensity (peak height) of each diffraction peak of the X-ray powder diffraction pattern; in particular, the stronger the absorption intensity, the better the separation, the smaller the 2 theta angle of the diffraction peak, the better the stability and repeatability it has, the more can be used to characterize this particular crystalline form; while diffraction peaks with larger 2 theta angles and/or poorer separations and/or weaker relative intensities may have larger fluctuations due to the influence of instruments, operating methods, sample purity, human factors and the like, and may not be repeatedly present in repeated experiments, so that such absorption peaks are not diffraction peaks necessary for the characterization of the present crystal form to those skilled in the art; more specifically, the invention follows the consensus of the field on the crystal form characterization, the selection of diffraction peaks comprehensively considers factors such as 2 theta angle, absorption intensity (peak height) and the like, and groups according to stability and repeatability.
It will also be appreciated by those skilled in the art that for Differential Scanning Calorimetric (DSC) and thermogravimetric analysis (TGA) curves of samples, the same batch and/or batch-to-batch samples will also be affected by the influence from instrumentation, detection conditions, detectors, etc. to produce fluctuations in the detection results, so that the present invention sets the fluctuation range of the onset of the endothermic peak, exothermic peak in the DSC profile to ±3 ℃ and the fluctuation range of the weightless value in the TGA profile to ±1%, in accordance with the consensus of the art for the characterization of crystalline forms.
Unless otherwise indicated, "room temperature" in the present invention means 25.+ -. 5 ℃ and thermogravimetric analysis curve (TGA) "in the present invention shows no significant weight loss" means that the weight loss is 1% or less before the end point temperature is detected.
The first aim of the invention is to provide a crystal form I of the compound 1 and a preparation method thereof, wherein the crystal form is shown to have better drug property.
In particular, form I of the aforementioned compound 1 has an XRPD pattern with stably occurring diffraction peaks at 2Θ of 3.7,7.4, 10.2, 12.0, 13.3, 14.1, 14.6, 14.9, 15.5, 16.2, 18.4, 18.8, 19.5, 20.5, 21.0, 22.5, 23.7, 24.1, 25.3, 26.7, 28.2±0.2°.
Further, form I of compound 1 described above also has an XRPD pattern having diffraction peaks at 2Θ of 8.7,9.6, 12.5, 16.7, 17.5, 27.4, 29.2, 30.2±0.2°.
Further, in some embodiments of the invention, the aforementioned form I of compound 1 has an XRPD pattern with diffraction peaks as shown in table 1 below:
table 1:
numbering device 2θ(±0.2°) Peak height% Numbering device 2θ(±0.2°) Peak height%
1 3.7 68.4％ 16 18.4 29.7％
2 7.4 10.6％ 17 18.8 56.4％
3 8.7 5.4％ 18 19.5 64.2％
4 9.6 2.5％ 19 20.5 100.0％
5 10.2 20.5％ 20 21.0 12.3％
6 12.0 17.6％ 21 22.5 18.6％
7 12.5 4.3％ 22 23.7 11.9％
8 13.3 23.6％ 23 24.1 26.5％
9 14.1 19.1％ 24 25.3 15.3％
10 14.6 11.1％ 25 26.7 7.7％
11 14.9 49.3％ 26 27.4 4.6％
12 15.5 11.8％ 27 28.2 6.7％
13 16.2 15.7％ 28 29.2 5.8％
14 16.7 4.7％ 29 30.2 4.9％
15 17.5 2.9％
Further, in some embodiments of the invention, the aforementioned form I of compound 1 has an XRPD pattern as shown in fig. 1.
Form I of the aforementioned compound 1, which has a Differential Scanning Calorimetry (DSC) with an onset of an endothermic peak at 122.18, 144.82 ±3 ℃.
Further, in some embodiments of the present invention, the aforementioned form I of compound 1 has a DSC profile as shown in figure 2.
Form I of the aforementioned compound 1, which loses weight 5.8±1% at 160 ℃ on its thermogravimetric analysis curve (TGA).
Further, in some embodiments of the invention, the aforementioned form I of compound 1 has a TGA profile as shown in fig. 3.
The second object of the present invention is to provide a crystal form II of compound 2, which is characterized by having good drug properties, and a process for preparing the same.
Compound 2 is a salt obtained after compound 1 is combined with sulfuric acid, and its structure is shown below:
wherein x is a number between 1 and 3.
Further, in the aforementioned crystal form II of compound 2, the structure of compound 2 may be:
specifically, in the form II of the compound 2, the compound 2 includes a lower hydrate, a solvate, a hydrate and a solvate thereof. In particular, form II of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2Θ of 5.8,8.7,9.7, 10.4, 10.6, 11.7, 14.2, 14.6, 17.6, 18.5, 19.2, 19.9, 20.6, 21.1, 23.6, 24.4, 25.6, 26.5, 28.1, 29.6, 30.0±0.2°.
Further, in some embodiments of the invention, the aforementioned form II of compound 2 has an XRPD pattern as shown in fig. 4.
Form II of the aforementioned compound 2, which is not the same form as form C disclosed in patent WO2017050224, is represented by: 1. form C of patent publication WO2017050224 has 2 characteristic peaks at 5.0 to 7.0 with 2θ angles of 5.775 and 6.012, whereas form II of compound 2 of the present invention has only 1 characteristic peak at 5.0 to 7.0 with 2θ angle of 5.8; 2. form C of patent publication WO2017050224 has 3 characteristic peaks at 2 theta angles of 10.292 and 10.874, etc. at 10.0 to 11.0, while form II of compound 2 of the present invention has 2 characteristic peaks at 2 theta angles of 10.4 and 10.6 at 10.0 to 11.0; 3. form C of patent publication WO2017050224 has 2 characteristic peaks at 11.0 to 12.0 with 2θ angles 11.336 and 11.872, whereas form II of compound 2 of the present invention has only 1 characteristic peak at 10.0 to 11.0 with 2θ angle 11.7; 4. the C crystal form of patent publication WO2017050224 has 1 characteristic peak with 2 theta angle of 22.638 at 22.0-23.0, while the crystal form II of the compound 2 of the present invention has no characteristic peak at 22.0-23.0.
Form II of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) with an onset of an endothermic peak at 70.71, 213.58, 269.69 ±3 ℃.
Further, in some embodiments of the present invention, the aforementioned form II of compound 2 has a DSC profile as shown in figure 5.
Form II of the aforementioned compound 2, which loses weight 5.1±1% at 140 ℃ on its thermogravimetric analysis curve (TGA).
Further, in some embodiments of the invention, the aforementioned form II of compound 2 has a TGA profile as shown in fig. 6.
The third object of the present invention is to provide a crystal form III of compound 2, which is characterized by having good drug properties, and a process for preparing the same.
In particular, form III of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2θ of 5.7, 11.5, 14.5, 19.9, 20.3, 23.3, 29.3±0.2°.
Further, the XRPD pattern of form III of compound 2 also has diffraction peaks at 2θ of 10.1, 17.4±0.2°.
Further, in some embodiments of the invention, the diffraction peaks of the XRPD patterns of form III of the aforementioned compound 2 are shown in table 2 below:
table 2:
numbering device 2θ(±0.2°) Peak height% Numbering device 2θ(±0.2°) Peak height%
1 5.7 100.0％ 6 19.9 6.6％
2 10.1 2.7％ 7 20.3 17.4％
3 11.5 30.9％ 8 23.3 25.7％
4 14.5 11.0％ 9 29.3 2.7％
5 17.4 2.5％
Further, in some embodiments of the invention, the aforementioned form III of compound 2 has an XRPD pattern as shown in fig. 8.
Form III of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) with an onset of an endothermic peak at 68.92, 209.64, 237.95 ±3 ℃.
Further, in some embodiments of the invention, the aforementioned form III of compound 2 has a DSC profile as shown in figure 9.
Form III of the aforementioned compound 2, which loses weight 5.9±1% at 150 ℃ according to thermogravimetric analysis (TGA).
Further, in some embodiments of the invention, the aforementioned form III of compound 2 has a TGA profile as shown in fig. 10.
The fourth object of the present invention is to provide a crystal form IV of the compound 2, which is shown to have better drug properties, and a preparation method thereof.
In particular, form IV of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2Θ of 5.6, 11.2, 14.1, 16.9, 19.7, 22.6, 25.5, 28.4 ± θ.2 °.
Further, form IV of the aforementioned compound 2 has an XRPD pattern with diffraction peaks at 21.9, 24.8±0.2° 2θ.
Further, in some embodiments of the invention, the aforementioned form IV of compound 2 has a XRPD pattern with diffraction peaks as shown in table 3 below:
table 3:
further, in some embodiments of the invention, form IV of the aforementioned compound 2 has an XRPD pattern as shown in fig. 12.
Form IV of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) with an onset of an endothermic peak at 82.43, 213.17 ±3 ℃.
Further, in some embodiments of the invention, form IV of compound 2 above has a DSC profile as shown in figure 13.
Form IV of the aforementioned compound 2, which loses weight 8.8±1% at 150 ℃ according to thermogravimetric analysis (TGA).
Further, in some embodiments of the invention, form IV of the aforementioned compound 2 has a TGA profile as shown in fig. 14.
A fifth object of the present invention is to provide a form V of compound 2, which is characterized by having a good drug property, and a process for preparing the same.
In particular, form V of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2θ of 4.6,5.5, 10.1, 11.2, 18.6, 19.5, 22.6, 22.8±0.2°.
Further, form V of compound 2, described above, also has a XRPD pattern with diffraction peaks at 2Θ of 9.7, 14.6, 15.4, 16.7, 23.8±0.2°.
Further, in some embodiments of the invention, form V of the aforementioned compound 2 has a XRPD pattern with diffraction peaks as shown in table 4 below:
table 4:
numbering device 2θ(±0.2°) Peak height% Numbering device 2θ(±0.2°) Peak height%
1 4.6 100.0％ 8 16.7 2.8％
2 5.5 44.2％ 9 18.6 13.7％
3 9.7 6.9％ 10 19.5 9.7％
4 10.1 7.9％ 11 22.6 12.8％
5 11.2 16.0％ 12 22.8 13.4％
6 14.6 3.8％ 13 23.8 4.7％
7 15.4 6.3％
Further, in some embodiments of the invention, form V of compound 2, described above, has an XRPD pattern as shown in figure 16.
Form V of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) with an onset of an endothermic peak at 62.92, 178.98 ±3 ℃.
Further, in some embodiments of the invention, form V of compound 2 has a DSC profile as shown in figure 17.
Form V of the aforementioned compound 2, which loses weight 7.4±1% at 150 ℃ on its thermogravimetric analysis curve (TGA).
Further, in some embodiments of the invention, form V of compound 2, described above, has a TGA profile as shown in fig. 18.
A sixth object of the present invention is to provide a form VI of compound 2, which exhibits superior drug properties, and a process for preparing the same.
In particular, form VI of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2θ of 5.4, 10.9, 16.5, 19.3, 22.1, 27.7±0.2°.
Further, form VI of compound 2, described above, has an XRPD pattern with diffraction peaks at 13.7, 19.9, 22.8, 24.9±0.2°.
Further, in some embodiments of the invention, the aforementioned form VI of compound 2 has an XRPD pattern with diffraction peaks as shown in table 5 below:
table 5:
further, in some embodiments of the invention, form VI of compound 2, described above, has an XRPD pattern as shown in figure 19.
Form VI of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) with an onset of an endothermic peak at 91.64, 209.85 ±3 ℃.
Further, in some embodiments of the invention, form VI of compound 2 above has a DSC profile as shown in figure 20.
Form VI of the aforementioned compound 2, which loses weight 7.9±1% at 190 ℃ according to thermogravimetric analysis (TGA).
Further, in some embodiments of the invention, form VI of compound 2, described above, has a TGA profile as shown in fig. 21.
The seventh object of the present invention is to provide a crystal form VII of the compound 2, which exhibits superior drug properties, and a method for preparing the same.
In particular, form VII of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2Θ of 5.7, 10.1, 11.4, 14.2, 17.0, 19.4, 20.0, 22.9±0.2°.
Further, form VII of the aforementioned compound 2 has an XRPD pattern with diffraction peaks at 2Θ of 13.0, 14.8, 15.1, 22.0, 25.1, 25.7, 28.7±0.2°.
Further, in some embodiments of the invention, the aforementioned form VII of compound 2 has an XRPD pattern with diffraction peaks as shown in table 6 below:
table 6:
numbering device 2θ(±0.2°) Peak height% Numbering device 2θ(±0.2°) Peak height%
1 5.7 100.0％ 9 19.4 4.8％
2 10.1 22.2％ 10 20.0 19.5％
3 11.4 43.7％ 11 22.0 4.3％
4 13.0 2.1％ 12 22.9 32.7％
5 14.2 14.4％ 13 25.1 1.8％
6 14.8 1.8％ 14 25.7 2.5％
7 15.1 4.3％ 15 28.7 3.0％
8 17.0 5.5％
Further, in some embodiments of the invention, form VII of the aforementioned compound 2 has an XRPD pattern as shown in figure 22.
Form VII of the aforementioned compound 2, having a Differential Scanning Calorimetry (DSC) with onset of an endothermic peak at 84.97, 212.60, 247.91 ±3 ℃.
Further, in some embodiments of the invention, form VII of the aforementioned compound 2 has a DSC profile as shown in figure 23.
Form VII of the aforementioned compound 2, having a thermogravimetric analysis (TGA) with a weight loss of 8.6±1% at 150 ℃.
Further, in some embodiments of the invention, form VII of the aforementioned compound 2 has a TGA profile as shown in fig. 24.
An eighth object of the present invention is to provide a crystalline form VIII of compound 2, which exhibits superior drug properties, and a process for preparing the same.
In particular, form VIII of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2θ of 4.8, 10.0, 11.4, 14.7, 16.0, 19.1, 21.9, 23.0±0.2°.
Further, form VIII of the aforementioned compound 2 has an XRPD pattern with diffraction peaks at 2θ of 6.2, 20.2, 21.0, 25.2, 26.1±0.2°.
Further, in some embodiments of the invention, the aforementioned crystalline form VIII of compound 2 has an XRPD pattern with diffraction peaks as shown in table 7 below:
table 7:
numbering device 2θ(±0.2°) Peak height% Numbering device 2θ(±0.2°) Peak height%
1 4.8 100.0％ 8 20.2 5.7％
2 6.2 9.5％ 9 21.0 6.9％
3 10.0 9.9％ 10 21.9 5.2％
4 11.4 10.9％ 11 23.0 15.3％
5 14.7 8.4％ 12 25.2 4.2％
6 16.0 12.1％ 13 26.1 4.7％
7 19.1 27.5％
Further, in some embodiments of the invention, form VIII of compound 2, described above, has an XRPD pattern as shown in figure 26.
Form VIII of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) curve with an onset of an endothermic peak at 69.79, 175.51 ±3 ℃.
Further, in some embodiments of the invention, form VIII of compound 2 has a DSC profile as shown in figure 27.
Form VIII of the aforementioned compound 2, which loses weight 7.5±1% at 130 ℃ according to thermogravimetric analysis (TGA).
Further, in some embodiments of the invention, form VIII of compound 2, has a TGA profile as shown in fig. 28.
A ninth object of the present invention is to provide a form IX of compound 2, which is characterized by having superior drug properties, and a process for preparing the same.
In particular, form IX of the aforementioned compound 2 has an XRPD pattern with diffraction peaks at 2θ of 5.3, 10.8, 16.2, 19.0, 21.7, 24.5, 27.3±0.2°.
Further, form IX of the aforementioned compound 2, which has an XRPD pattern with stably occurring diffraction peaks at 2θ of 17.9, 19.7, 20.0, 20.3, 22.2±0.2°.
Further, in some embodiments of the invention, the aforementioned form IX of compound 2 has an XRPD pattern with diffraction peaks as shown in table 8 below:
table 8:
numbering device 2θ(±0.2°) Peak height% Numbering device 2θ(±0.2°) Peak height%
1 5.3 100.0％ 7 20.0 1.8％
2 10.8 58.9％ 8 20.3 1.7％
3 16.2 42.1％ 9 21.7 93.9％
4 17.9 1.2％ 10 22.2 2.1％
5 19.0 13.0％ 11 24.5 16.5％
6 19.7 2.3％ 12 27.3 17.2％
Further, in some embodiments of the invention, form IX of compound 2, supra, has an XRPD pattern as shown in figure 29.
Form IX of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) with onset of an endothermic peak at 79.48, 207.40, 272.61 ±3 ℃.
Further, in some embodiments of the invention, form IX of compound 2 above has a DSC profile as shown in figure 30.
Form IX of the aforementioned compound 2, which loses 8.4±1% of weight at 140 ℃ on its thermogravimetric analysis curve (TGA).
Further, in some embodiments of the invention, form IX of compound 2 above has a TGA profile as shown in figure 31.
A tenth object of the present invention is to provide a crystal form X of compound 2, which exhibits superior drug properties, and a method for preparing the same.
Specifically, form X of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2θ of 4.9,6.5, 10.5, 11.6, 14.9±0.2°.
Further, in some embodiments of the invention, form X of compound 2, described above, has an XRPD pattern as shown in figure 32.
Form X of the aforementioned compound 2, which has a Differential Scanning Calorimetry (DSC) with an onset of an endothermic peak at 64.06, 170.14 ±3 ℃.
Further, in some embodiments of the invention, form X of compound 2 has a DSC profile as shown in figure 33.
Form X of the aforementioned compound 2, its thermogravimetric analysis (TGA) shows a weight loss of 9.1±1% at 140 ℃.
Further, in some embodiments of the invention, form X of compound 2, described above, has a TGA profile as shown in figure 34.
An eleventh object of the present invention is to provide a crystalline form XI of Compound 2 and a preparation method thereof.
In particular, form XI of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 2θ of 5.3, 10.4, 15.7, 18.6, 19.7, 29.5±0.2°.
Further, form XI of compound 2, described above, has an XRPD pattern with diffraction peaks at 29 of 12.4, 12.8, 15.1, 16.3, 16.8, 17.4, 21.0, 22.8, 23.9, 24.5, 25.9, 27.9±0.2°.
Further, in some embodiments of the invention, the aforementioned crystalline form XI of Compound 2 has an XRPD pattern with diffraction peaks as shown in Table 9 below:
table 9:
numbering device 2θ(±0.2°) Peak height% Numbering device 2θ(±0.2°) Peak height%
1 5.3 8.0％ 10 18.6 5.1％
2 10.4 38.8％ 11 19.7 100.0％
3 12.4 2.0％ 12 21.0 3.7％
4 12.8 4.2％ 13 22.8 3.3％
5 15.1 1.6％ 14 23.9 3.3％
6 15.7 12.0％ 15 24.5 2.2％
7 16.3 3.4％ 16 25.9 3.0％
8 16.8 2.2％ 17 27.9 1.0％
9 17.4 2.9％ 18 29.5 13.6％
Further, in some embodiments of the invention, form XI of compound 2 has an XRPD pattern as shown in FIG. 35.
A twelfth object of the present invention is to provide a crystalline form XII of compound 2 and a method for preparing the same.
In particular, form XII of the aforementioned compound 2 has an XRPD pattern with stably occurring diffraction peaks at 5.9, 10.1, 11.8, 14.8, 20.1, 20.4, 23.7±0.2°.
Further, form XII of compound 2 described above also has a diffraction pattern with diffraction peaks at 2Θ of 11.0, 12.7, 15.4, 16.0, 16.6, 18.6, 19.1, 22.5, 25.7, 26.8, 28.3, 29.6±0.2°.
Further, in some embodiments of the invention, the aforementioned form XII of compound 2 has a diffraction peak profile of the XRPD pattern as shown in table 10 below:
table 10:
further, in some embodiments of the invention, form XII of compound 2 described above has an XRPD pattern as shown in figure 36.
The invention relates to a series of specific crystal forms, which are crystal forms of a salt formed by combining a compound 1 and two sulfuric acid molecules;
a medicament comprising any one or more of the crystalline forms of compound 1 or any one or more of the crystalline forms of compound 2 of the present invention.
A thirteenth object of the present invention is to provide a drug substance containing any one or more crystal forms of the compound 1 or any one or more crystal forms of the compound 2 according to the present invention. Based on the foregoing beneficial effects of any one or more of the crystalline forms of compound 1 or any one or more of the crystalline forms of compound 2 of the present invention, the drug substance containing the crystalline form also exhibits beneficial effects (e.g., stability, water solubility, etc.) substantially consistent with the crystalline form, and in particular, the drug substance may be compound 1 and/or other salt forms of compound 1, which other salt forms of compound 1 are pharmaceutically acceptable salts common in the art, including but not limited to salts with bases, such as: potassium, calcium, magnesium, triethylamine, and the like, and salts with acids such as: hydrochloride, sulfate, phosphate, mesylate, besylate, p-toluenesulfonate, and the like; more specifically, the bulk drug contains any value of 0.01 to 99.99% of the mass percentage of the compound I and/or the compound II and/or the compound III and/or the compound IV and/or the compound V and/or the compound VI and/or the compound VII and/or the compound VIII and/or the compound IX and/or the compound X and/or the compound XI and/or the compound XII, and further contains any value of 1.00 to 99.00% of the mass percentage of the compound I and/or the compound III and/or the compound IV and/or the compound V and/or the compound VI and/or the compound VII and/or the compound VIII and/or the compound IX and/or the compound X and/or the compound XI and/or the compound XII.
A fourteenth object of the present invention is to provide a pharmaceutical composition composed of the aforementioned bulk drugs and pharmaceutically acceptable excipients including, but not limited to, at least one of fillers, binders, disintegrants, lubricants, etc.; specifically, based on the beneficial effects of any one or more crystal forms of the compound 1 or any one or more crystal forms of the compound 2 according to the present invention, the beneficial effects are finally embodied in the pharmaceutical composition; more specifically, the pharmaceutical composition contains the bulk drug with a mass percentage of 1.00-99.00%, further contains the bulk drug with a mass percentage of 5.00-95.00%, and further contains the bulk drug with a mass percentage of 10.00-90.00%.
In summary, the form I of the compound 1 and the forms II to XII of the compound 2 of the present invention have a certain pharmaceutical prospect, and therefore, if the detection means prove that the form I of the compound 1 and the form II to XII of the compound 2 exist in the above-mentioned raw materials and/or pharmaceutical compositions, the use of the form I of the compound 1 and the form II to XII of the compound 2 provided by the present invention should be considered. The detection means may further include Differential Scanning Calorimetry (DSC), infrared spectroscopy (IR), raman spectroscopy (Raman), solid State Nuclear Magnetic Resonance (SSNMR) and other methods, alone or in combination, in addition to the aforementioned X-ray powder diffraction, to confirm the detection methods of form I of the compound 1 and form II to form XII of the compound 2 according to the present invention, and may use methods commonly used by those skilled in the art to remove the effects caused by pharmaceutical excipients, such as subtraction spectroscopy.
The invention relates to the application of any one or more crystal forms of the compound 1 or any one or more crystal forms of the compound 2 in preparing medicines for treating cancers.
Such cancers include, but are not limited to, medulloblastoma, pancreatic cancer, intestinal gastric cancer, rectal cancer, ovarian cancer, and prostate cancer.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the invention discloses a crystal form I of a compound 1 and a preparation method thereof, wherein the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
2. the crystal form II of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
3. the crystal form III of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
4. the crystal form IV of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
5. the crystal form V of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
6. the crystal form VI of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
7. The crystal form VII of the compound 2 and a preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
8. the crystal form VIII of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
9. the crystal form IX of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
10. the crystal form X of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable prospect of patent medicine;
11. the first time discloses a crystal form XI of the compound 2 and a preparation method thereof;
12. the first time discloses a crystal form XII of the compound 2 and a preparation method thereof;
13. the invention provides a bulk drug which contains at least one of the crystal forms II-XII of the compound 1 and the compound 2, and the bulk drug has the beneficial effects basically consistent with the crystal forms II-XII of the compound 1 and the compound 2;
14. the invention provides a pharmaceutical composition which consists of the bulk drug and pharmaceutically acceptable auxiliary materials and has the beneficial effects basically consistent with the crystal forms II-XII of the compound 1 and the compound 2.
Drawings
Fig. 1: XRPD pattern of compound 1 form I;
fig. 2: DSC profile of compound 1 form I;
fig. 3: TGA profile of compound 1 form I;
fig. 4: XRPD pattern of compound 2 form II;
fig. 5: DSC profile of compound 2 form II;
fig. 6: TGA profile of compound 2 form II;
fig. 7: XRPD comparison of form II of compound 2 from example 3 and form II of compound 2 from example 4;
fig. 8: XRPD pattern of compound 2 form III;
fig. 9: DSC profile of compound 2 form III;
fig. 10: TGA profile of compound 2 form III;
fig. 11: XRPD comparison of form III of compound 2 prepared in example 5 and form III of compound 2 prepared in example 6;
fig. 12: XRPD pattern of compound 2 form IV;
fig. 13: DSC profile of compound 2 form IV;
fig. 14: TGA profile of compound 2 form IV;
fig. 15: XRPD comparison of form IV of compound 2 from example 7 and form IV of compound 2 from example 8
Fig. 16: XRPD pattern of compound 2 form V;
fig. 17: DSC profile of compound 2 form V;
fig. 18: TGA profile of compound 2 form V;
fig. 19: XRPD pattern of compound 2 form VI;
fig. 20: DSC profile of compound 2 form VI;
Fig. 21: TGA profile of compound 2 form VI;
fig. 22: XRPD pattern of compound 2 form VII;
fig. 23: DSC profile of form VII of Compound 2;
fig. 24: TGA profile of compound 2 form VII;
fig. 25: XRPD comparison of form VII of compound 2 from example 11 and form VII of compound 2 from example 12;
fig. 26: XRPD pattern of compound 2 form VIII;
fig. 27: DSC profile of form VIII of compound 2;
fig. 28: TGA profile of compound 2 form VIII;
fig. 29: XRPD pattern of compound 2 form IX;
fig. 30: DSC profile of compound 2 form IX;
fig. 31: TGA profile of compound 2 form IX;
fig. 32: XRPD pattern of compound 2 form X;
fig. 33: DSC profile of compound 2 form X;
fig. 34: TGA profile of compound 2 form X;
fig. 35: XRPD pattern of compound 2 form XI;
fig. 36: XRPD pattern of compound 2 form XII;
fig. 37: XRPD patterns of compound 2 form XII and form III are compared.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but embodiments of the invention are not limited thereto.
Detection conditions
X-ray powder diffraction
X-ray powder diffractometer: bruker D8 Advance;
2θ scan angle: from 3 ° to 45 °;
scanning step length: 0.02 °;
exposure time: 0.2 seconds;
light pipe voltage and current: 40KV and 40mA.
Differential scanning calorimetric analysis
Differential scanning calorimeter: TA Discovery 2500 (TA, US);
heating rate: 10 ℃/min;
the detection method comprises the following steps: the sample was weighed precisely and placed in a DSC Tzero sample pan, heated to 350℃and purged with nitrogen in the oven at a rate of 50mL/min.
Thermogravimetric analysis
Thermogravimetric analyzer: TA Discovery 55 (TA, US);
the detection method comprises the following steps: the samples were placed in equilibrated open aluminum sample trays and automatically weighed in a heated oven. The sample was heated to 400℃at a rate of 10℃per minute with a nitrogen purge rate of 60mL/min at the sample and 40mL/min at the balance.
Example 1 preparation of Compound 1
Compound 1 was prepared by the method disclosed in example 1 of reference patent WO 2017050224.
EXAMPLE 2 preparation of Compound 1 Crystal form I
14g of compound 1 prepared by the method of example 1 is weighed, added with (84 mL of ethanol+16 mL of ethyl acetate) binary solvent, stirred for 1 day at 50 ℃, and the suspension is centrifugally separated and dried at room temperature under vacuum to obtain light yellow solid, wherein the XRPD spectrum of the obtained crystal form I is shown in figure 1, the DSC spectrum is shown in figure 2, and the TGA spectrum is shown in figure 3.
EXAMPLE 3 preparation of Compound 2 form II
Form I (5 g,10.9 mmol) prepared by the method of example 2 was dissolved in acetone (50 mL) and stirred for 15 min at 50 ℃. Sulfuric acid (3 m,7.6 ml) was slowly added for about 5 minutes, and the mixture was stirred at 25 ℃ for 1 hour. The mixture was filtered, the solid was rinsed with acetone (2 mL), dried under vacuum at 35 ℃ after suction to give a solid, 20mg of the solid was suspended in 1mL of methyl tert-butyl ether, stirred at room temperature for 7 days, the suspension was centrifuged and dried under vacuum at room temperature to give form II of the target compound 2, the XRPD pattern of the obtained form II was shown in fig. 4, the DSC pattern was shown in fig. 5, and the TGA pattern was shown in fig. 6.
The crystal form II of the prepared compound is not the same as the C crystal form disclosed in patent WO2017050224, and is specifically expressed in the following steps: 1. form C of patent publication WO2017050224 has 2 characteristic peaks at 5.0 to 7.0 with 2θ angles of 5.775 and 6.012, whereas form II of compound 2 of the present invention has only 1 characteristic peak at 5.0 to 7.0 with 2θ angle of 5.8; 2. form C of patent publication WO2017050224 has 3 characteristic peaks at 2 theta angles of 10.292 and 10.874, etc. at 10.0 to 11.0, while form II of compound 2 of the present invention has 2 characteristic peaks at 2 theta angles of 10.4 and 10.6 at 10.0 to 11.0; 3. form C of patent publication WO2017050224 has 2 characteristic peaks at 11.0 to 12.0 with 2θ angles 11.336 and 11.872, whereas form II of compound 2 of the present invention has only 1 characteristic peak at 10.0 to 11.0 with 2θ angle 11.7; 4. the C crystal form of patent publication WO2017050224 has 1 characteristic peak with 2 theta angle of 22.638 at 22.0-23.0, while the crystal form II of the compound 2 of the present invention has no characteristic peak at 22.0-23.0.
EXAMPLE 4 preparation of Compound 2 form II
Form I (5 g,10.9 mmol) prepared by the method of example 2 was dissolved in acetone (50 mL) and stirred for 15 min at 50 ℃. Sulfuric acid (3 m,7.6 ml) was slowly added for about 5 minutes, and the mixture was stirred at 25 ℃ for 1 hour. The mixture was filtered, the solid was rinsed with acetone (2 mL), dried under vacuum at 35 ℃ after suction to give a solid, 20mg of the solid was taken, suspended in 1mL of diethyl ether, stirred at room temperature for 7 days, the suspension was centrifuged, and dried under vacuum at room temperature to give crystalline form II of the target compound 2.
A comparison of the XRPD patterns of the resulting form II is shown in figure 7.
EXAMPLE 5 preparation of Compound 2 form III
20mg of compound 2 form II prepared by the method of example 3 is weighed, 0.5mL of binary solvent (0.1 mL of ethylene glycol methyl ether plus 0.4mL of n-propanol) is added, the suspension is stirred for 7 days at room temperature, the suspension is centrifugally separated and dried at room temperature under vacuum, and compound 2 form III is obtained, the XRPD spectrum of the obtained compound 2 form III is shown in figure 8, the DSC spectrum is shown in figure 9, and the TGA spectrum is shown in figure 10.
EXAMPLE 6 preparation of Compound 2 form III
20mg of the crystalline form II of the compound 2 prepared in the method of example 3 was weighed, suspended in 1mL of tetrahydrofuran, stirred at 50℃for 1 day, and the suspension was centrifuged and dried at room temperature under vacuum to obtain the crystalline form III of the target compound 2.
A comparison of the XRPD patterns of the resulting form III is shown in figure 11.
EXAMPLE 7 preparation of Compound 2 form IV
20mg of the compound 2 form II prepared by the method of example 3 is weighed and suspended in 1mL of ethylene glycol dimethyl ether, the suspension is centrifugally separated after being stirred for 1 day at 50 ℃, and the suspension is dried in vacuum at room temperature to obtain the compound 2 form IV, wherein an XRPD spectrum of the obtained compound 2 form IV is shown in figure 12, a DSC spectrum is shown in figure 13, and a TGA spectrum is shown in figure 14.
EXAMPLE 8 preparation of Compound 2 form IV
60mg of the compound 2 form II prepared by the method of example 3 was weighed, 0.5mL of a binary solvent (0.2 mL of ethylene glycol methyl ether +0.3mL of n-hexane) was added, and after suspending and stirring at 50℃for 1 day, the suspension was centrifugally separated and dried at room temperature under vacuum to obtain the compound 2 form IV.
A comparison of the XRPD patterns of the resulting form IV is shown in figure 15.
EXAMPLE 9 preparation of Compound 2 form V
20mg of compound 2 form II prepared by the method of example 3 is weighed and suspended in 1mL of n-propanol, after suspending and stirring for 1 day at 50 ℃, the suspension is centrifugally separated and dried at room temperature under vacuum, and compound 2 form V is obtained, wherein the XRPD spectrum of the obtained compound 2 form V is shown in FIG. 16, the DSC spectrum is shown in FIG. 17, and the TGA spectrum is shown in FIG. 18.
EXAMPLE 10 preparation of Compound 2 form VI
20mg of the compound 2 form II prepared by the method of example 3 is weighed, 0.1mL of dimethylformamide is added dropwise at room temperature until the compound 2 form II is completely dissolved, then 0.4mL of ethyl acetate is added dropwise until solid precipitation occurs, centrifugal separation is carried out, vacuum drying is carried out at room temperature, and then the compound 2 form VI is obtained, an XRPD spectrum of the obtained compound 2 form VI is shown in figure 19, a DSC spectrum is shown in figure 20, and a TGA spectrum is shown in figure 21.
Example 11 preparation of Compound 2 form VII
20mg of compound 2 form II prepared by the method of example 3 is weighed, 0.5mL of binary solvent (0.1 mL of methanol+0.4 mL of n-propanol) is added, after suspending and stirring for 1 day at 50 ℃, the suspension is centrifugally separated and dried at room temperature under vacuum to obtain compound 2 form VII, the XRPD spectrum of the obtained form VII is shown in FIG. 22, the DSC spectrum is shown in FIG. 23, and the TGA spectrum is shown in FIG. 24.
Example 12 preparation of Compound 2 form VII
20mg of the compound 2 crystal form II prepared by the method of example 3 is weighed, 0.1mL of dimethylformamide is added dropwise at room temperature until the compound 2 crystal form II is completely dissolved, then 0.3mL of diethyl ether is added dropwise until solid precipitation occurs, and after centrifugal separation, the compound 2 crystal form VII is obtained by vacuum drying at room temperature.
A comparison of the XRPD patterns of the resulting form VII is shown in figure 25.
EXAMPLE 13 preparation of Compound 2 form VIII
20mg of compound 2 form II prepared by the method of example 3 is weighed and suspended in 1mL of ethyl formate, after suspending and stirring for 1 day at 50 ℃, the suspension is centrifugally separated and dried in vacuum at room temperature to obtain compound 2 form VIII, the XRPD spectrum of the obtained form VIII is shown in figure 26, the DSC spectrum is shown in figure 27, and the TGA spectrum is shown in figure 28.
EXAMPLE 14 preparation of Compound 2 form IX
22.8mg of the compound 2 form II prepared by the method of example 3 is weighed, dimethylformamide is added dropwise until the compound 2 form II is completely dissolved, the solution is placed in dioxane atmosphere and kept stand at room temperature until solids are separated out, a system with the solids separated out is centrifugally separated and then dried at room temperature in vacuum, and the compound 2 form IX is obtained, an XRPD spectrum of the obtained compound 2 form IX is shown in FIG. 29, a DSC spectrum is shown in FIG. 30, and a TGA spectrum is shown in FIG. 31.
EXAMPLE 15 preparation of Compound 2 form X
20mg of compound 2 form II prepared by the method of example 3 is weighed and suspended in 1mL of isopropanol, after suspending and stirring for 7 days at room temperature, the suspension is centrifugally separated and dried at room temperature in vacuum, and compound 2 form X is obtained, wherein the XRPD spectrum of the obtained compound 2 form X is shown in figure 32, the DSC spectrum is shown in figure 33, and the TGA spectrum is shown in figure 34.
EXAMPLE 16 preparation of Compound 2 form XI
20mg of the compound 2 form II prepared by the method of example 3 is weighed, added into an EP tube, 0.1mL of dimethylformamide is added dropwise until the compound 2 form II is completely dissolved, the solution is left open at room temperature until the solvent is completely volatilized, and the XRPD pattern of the obtained compound 2 form XI is shown in FIG. 35.
EXAMPLE 17 preparation of Compound 2 form XII
20mg of form II of compound 2 prepared as described in example 3 was weighed and dried in vacuo at 90℃to give form XII of compound 2, which was allowed to stand at room temperature for 7 days to detect a new solid, which was shown as form III, and the XRPD pattern of the obtained form XII is shown in FIG. 36.
The spectrum pairs of form III and form XII of compound 2 are shown in fig. 37.
EXAMPLE 18 stability Studies
A certain amount of sample to be measured is weighed and placed in a surface dish, and is respectively placed under high temperature (60 ℃), high humidity (25 ℃,92.5% RH), illumination (25 ℃,4500 Lux) and acceleration (40 ℃,75% RH) conditions, and sampling is carried out for 14 days for XRPD characterization.
The stability studies under high temperature (60 ℃), high humidity (25 ℃, 92% rh), light (25 ℃,4500 Lux), and accelerated conditions (40 ℃,75% rh) were performed on form I, form II, form III, form IV, and forms a and C of patent WO2017050224, respectively, and the results are shown in table 11:
Table 11: stability study results
The results show that the crystal forms I, II, III and IV have higher stability under high temperature, high humidity, illumination and acceleration conditions. The crystal forms I, II, III and IV can be used as intermediate crystal forms to further prepare other stable crystal forms in part; while the form a of WO2017050224 is stable at high temperature, high humidity and light, the properties change under accelerated conditions, showing that it exhibits instability upon long-term storage, while the form C of WO2017050224 shows that its properties change under light and accelerated conditions, showing that it exhibits instability upon long-term storage.
In addition, the inventors have found during the course of experiments and further studies that:
the crystal form V is obtained by heating and stirring crystal form II in n-propanol for a long time and crystallizing, and the person skilled in the art can understand that the crystal form V has higher stability;
form VI can be obtained by dissolving form II in dimethylformamide followed by dropwise addition of ethyl acetate for solvency crystallization, as will be appreciated by those skilled in the art, form VI has a higher stability;
the crystal form VII is obtained by heating the crystal form II in a binary solvent (methanol and n-propanol) and stirring for a long time, and crystallizing, and as can be understood by those skilled in the art, the crystal form VII has higher stability;
The crystal form VIII is obtained by heating and stirring crystal form II in ethyl formate for a long time and crystallizing, and the person skilled in the art can understand that the crystal form VIII has higher stability;
form IX is obtained by suspending form II in a mixed solvent of dimethylformamide and dioxane, as will be appreciated by those skilled in the art, form IX has a higher stability;
form X is obtained by suspending form II in isopropanol, as will be appreciated by those skilled in the art, form X has a higher stability;
in the experimental process, the inventor captures an intermediate metastable crystal form (crystal form XII) in the forming process, and the intermediate metastable crystal form can be transited to finally obtain a crystal form II or a crystal form III, and further can know that the crystal form II or the crystal form III has higher stability.
In summary, the crystal forms of the compound 1 or the compound 2 have at least one of stability, solubility and other effects, and provide various intermediate products and/or raw material drug choices for mass production of raw material drugs and downstream processes (such as preparation processes) of pharmaceutical products.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (23)

1. A crystalline form II of compound 2, wherein, in the crystalline form II of compound 2, the structure of compound 2 is as follows:
wherein x is a number between 1 and 3;
the XRPD pattern of form II of compound 2 has a diffraction peak at 5.8,8.7,9.7,10.4,10.6,11.7,14.2,14.6,17.6,18.5,19.2,19.9,20.6,21.1,23.6,24.4,25.6,26.5,28.1,29.6,30.0 ±2° 2θ.
2. Form II of compound 2 according to claim 1, characterized in that the XRPD pattern of form II of compound 2 is as shown in fig. 4.
3. Form II of compound 2 according to claim 1, characterized in that said form II of compound 2 has only 1 characteristic peak between 5.0 and 7.0, only 2 characteristic peaks between 10.0 and 11.0, only 1 characteristic peak between 11.0 and 12.0, and no characteristic peak between 22.0 and 23.0.
4. A form II of compound 2 according to any one of claims 1-3, characterized in that the DSC profile of form II of compound 2 has a starting point of the endothermic peak at 70.71,213.58,269.69 ±3 ℃.
5. A form II of compound 2 according to any one of claims 1 to 3, characterized in that the DSC profile of form II of compound 2 is shown in figure 5.
6. A form II of compound 2 according to any one of claims 1-3, characterized in that the TGA profile of form II of compound 2 loses weight 5.1±1% at 140 ℃.
7. A form II of compound 2 according to any one of claims 1-3, characterized in that the TGA profile of form II of compound 2 is shown in figure 6.
8. A form III of compound 2, wherein the XRPD pattern of form III of compound 2 has a diffraction peak at 5.7,11.5,14.5,19.9,20.3,23.3,29.3 ±0.2° 2Θ
Wherein x is a number between 1 and 3;
the diffraction peaks for the XRPD pattern of crystalline form III of compound 2 are shown in the table below:
numbering device 2θ(±0.2°) Numbering device 2θ(±0.2°) 1 5.7 6 19.9 2 10.1 7 20.3 3 11.5 8 23.3 4 14.5 9 29.3 5 17.4
。
9. Form III of compound 2 according to claim 8, characterized in that the XRPD pattern of form III of compound 2 is as shown in fig. 8.
10. Form III of compound 2 according to claim 8 or 9, characterized in that the DSC profile of form III of compound 2 has a starting point of the endothermic peak at 68.92,209.64,237.95 ±3 ℃.
11. Form III of compound 2 according to claim 8 or 9, characterized in that the DSC profile of form III of compound 2 is shown in figure 9.
12. Form III of compound 2 according to claim 8 or 9, characterized in that the TGA profile of form III of compound 2 loses weight 5.9±1% at 150 ℃.
13. Form III of compound 2 according to claim 8 or 9, characterized in that the TGA profile of form III of compound 2 is shown in figure 10.
14. Form IV of compound 2, characterized in that the XRPD pattern of form IV of compound 2 has a diffraction peak at 5.6,11.2,14.1,16.9,19.7,22.6,25.5,28.4 ±0.2° 2Θ
Wherein x is a number between 1 and 3;
the diffraction peaks for the XRPD pattern of form IV of compound 2 are shown in the following table:
15. form IV of compound 2 according to claim 14, characterized in that the XRPD pattern of form IV of compound 2 is as shown in figure 12.
16. Form IV of compound 2 according to claim 14 or 15, characterized in that the DSC profile of form IV of compound 2 has an onset of an endothermic peak at 82.43,213.17 ±3 ℃.
17. Form IV of compound 2 according to claim 14 or 15, characterized in that the DSC profile of form IV of compound 2 is shown in figure 13.
18. Form IV of compound 2 according to claim 14 or 15, characterized in that the TGA profile of form IV of compound 2 loses 8.8±1% weight at 150 ℃.
19. Form IV of compound 2 according to claim 14 or 15, characterized in that the TGA profile of form IV of compound 2 is shown in figure 14.
20. A pharmaceutical formulation comprising other salt forms of compound 1, wherein the pharmaceutical formulation comprises a crystalline form of compound 2 according to any one of claims 1-19;
the other salt forms do not include sulfate salts.
21. A pharmaceutical composition, characterized in that the pharmaceutical composition consists of the bulk drug of claim 20 and pharmaceutically acceptable auxiliary materials; the pharmaceutically acceptable auxiliary materials comprise at least one of filler, adhesive, disintegrating agent and lubricant.
22. A medicament comprising the crystalline form of any one of claims 1-19.
23. Use of the crystalline form of any one of claims 1-19 in the preparation of an SMO inhibitor.
CN202180022477.8A 2020-03-27 2021-03-15 Salt form and crystal form of SMO inhibitor compound and preparation method thereof Active CN115298172B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
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CN104945377A (en) * 2014-03-24 2015-09-30 南京明德新药研发股份有限公司 Quinoline derivatives used as SMO inhibitors
WO2015144001A1 (en) * 2014-03-24 2015-10-01 南京明德新药研发股份有限公司 Quinoline derivatives as smo inhibitors
WO2017050224A1 (en) * 2015-09-21 2017-03-30 广东众生药业股份有限公司 Salt form and crystal form of quinoline derivative, preparation method therefor, and intermediate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104945377A (en) * 2014-03-24 2015-09-30 南京明德新药研发股份有限公司 Quinoline derivatives used as SMO inhibitors
WO2015144001A1 (en) * 2014-03-24 2015-10-01 南京明德新药研发股份有限公司 Quinoline derivatives as smo inhibitors
WO2017050224A1 (en) * 2015-09-21 2017-03-30 广东众生药业股份有限公司 Salt form and crystal form of quinoline derivative, preparation method therefor, and intermediate

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